Messenger RNA (mRNA) translation initiation plays a critical role in the regulation of cell growth and malignant transformation because expression of most oncogenic and cell growth regulatory proteins is translationally regulated (Flynn et al., 1996, Cancer Surv. 27:293; Sonenberg et al., 1998, Curr. Opin. Cell Biol. 10:268). For this reason, translation initiation is a tightly regulated cellular process. Failure in negative regulation of translation initiation may lead to the induction, onset and progression of cancer (Donze et al., 1995, Embo J. 14: 3828; Rosenwald, 1996, Bioessays 18: 243-50; De Benedetti et al., 2004, Oncogene 23: 3189-99; and Rosenwald, 2004, Oncogene 23:3230). Inhibition of poorly-regulated translation initiation also can cause reversion of transformed phenotypes (Jiang et al., 2003, Cancer Cell Int. 3:2; Graff et al., 1995, Int. J. Cancer 60:255). The eIF2 GTP Met-tRNA, complex (also known as the ternary complex) is a key positive regulator of translation initiation. Limiting its availability curtails initiation of new rounds of protein translation. While translation of many oncogenic proteins and other cell growth factors relies heavily on the ternary complex, the same is not true of housekeeping genes, for which reason food, nutriceutical and medicinal products that help to limit the amount, availability or activity of the ternary complex potentially offer a safe means of preventing and treating disease. In addition, expression of certain tumor suppressors and pro-apoptotic genes and/or proteins actually increases in the presence of inhibitors of the ternary complex or, more generally, of translation initiation. Reduced translation of oncogenic proteins, especially combined with up-regulation of tumor suppressors and pro-apoptotic genes, tends overall to prevent and/or repress the malignant phenotype.
Eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid (n-3 PUFA), is found in large quantities in oil derived from fish, particularly those of wild populations native to cold oceanic waters. Farmed fish typically contain far lower levels of n-3 PUFAs than do wild fish. It has been observed that when marine fish oil is administered to human prostate cancer patients, eIf2α is phosphorylated, suggesting that the availability of functional eIF2 to the ternary complex has been reduced, in accordance with the findings using EPA and synthetic inhibitors of the ternary complex in animal models or cell-based experimental systems. Accordingly, dietary supplements that contain translation initiation inhibitors represent attractive commercial products for treatment and/or prevention of cancer and/or proliferative diseases in which abnormal cell proliferation is a characteristic pathological abnormality. Such dietary supplements can also act as translation initiation regulators, and represent attractive commercial products for treatment and/or prevention of metabolic diseases such as obesity and diabetes.
Fish oil from a variety of sources is widely available to consumers as a food product or nutritional supplement. The oil, or oil-derived fractions or components, contained in different production lots, batches, samples or doses of a product may vary in quality or potency, depending on their sources (e.g., climates, fish species or growth conditions, suppliers) or processing conditions. The same even may be true of the contents of a single lot, batch, sample or dose of product. Other food, nutriceutical or medicinal products that contain natural or synthetic inhibitors of translation initiation can vary in quality or potency for similar reasons.
There is a need for quality control and/or assurance with respect to a product's physiological or medicinal effects on potential consumers.